Diabetes%20mellitus Treatment

• Overall target is to improve and maintain quality of life and prevent complications and early death
  • Short-term: Relief of symptoms and acute complications
  • Long-term: Achieve target blood sugar level, reduce concurrent risk factors, identify and treat chronic complications
• Diabetes mellitus is a progressive disease where pharmacologic agents are likely to become a necessity in most patients even if they are compliant to dietary and physical activity recommendations
• Fasting hyperglycemia should be controlled and is necessary in stabilizing HbA1c in poorly controlled patients with diabetes
  • Postprandial hyperglycemia should be identified and managed in patients with suboptimal glycemic control (HbA1c 6.5-7.5%)
• Reassess and modify patient's treatment regularly (every 3 to 6 months) to prevent therapeutic inertia
• Treatment plan must be individualized based on patient's age, cognitive abilities, school or work schedule and conditions, health beliefs, support systems, eating patterns, physical activity, social situation, financial situation, cultural factors, literacy including mathematical literacy, diabetes history, comorbidities, disabilities, health priorities, preferences for care, access to health care services and life expectancy
• Treatment types and devices prescribed depend on the patient's specific needs, preferences and patient's/caregiver's skill level
• Choice of treatment is influenced by the following factors:
  • Individualized glycemic and weight goals
  • Access, cost, availability of medication, lifestyle choices
  • Impact on weight, hypoglycemia and cardiorenal protection
  • Underlying physiological factors
  • Adverse effects of medications
  • Complexity of regimens (eg frequency, mode of administration)
  • Regimen choice to optimize medication use and reduce treatment discontinuation

Therapy for Type 1 Diabetes Mellitus

• Consists of intensive insulin therapy which administers multiple-dose prandial (injected or inhaled) and basal insulin injections or continuous subcutaneous insulin infusion (CS II) therapy, matching prandial insulin to carbohydrate intake, premeal glucose and expected activity, and using rapid-acting insulin analogs in reducing hypoglycemic risk
• Insulin analogs (or inhaled insulin) are preferred over injectable human insulins to minimize risk of hypoglycemia
• Teplizumab-mzwv infusion should be considered in patients ≥8 years old with stage 2 type 1 diabetes mellitus to delay the onset of symptomatic stage 3 type 1 diabetes mellitus

Therapy for Type 2 Diabetes Mellitus

• Goals of pharmacological therapy include:
  • To achieve patient-individualized glucose targets
    • A1c goal of ≤6.5-7% is recommended for most individuals
    • A1c goal may be less stringent if risk of hypoglycemia is high, in the presence of comorbidities, with a long duration of diabetes mellitus, in frail or old adults, or if life expectancy is short
  • To reduce risk of hypoglycemia
  • To facilitate weight loss in obese/overweight patients and to prevent additional gain in weight
  • To prevent appearance of cardiovascular disease and other comorbidities, including reduction of cardiorenal risk in high-risk patients with type 2 diabetes mellitus

• Based on the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) 2022 consensus report and the 2024 ADA guideline, choosing appropriate pharmacologic treatment for diabetes mellitus and subsequent treatment intensification should utilize shared decision-making and should have a patient-centered approach that includes consideration of the following factors:
  • Significant comorbidities eg atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease and heart failure
  • Risk of hypoglycemia
  • Effects on body weight
  • Side effects of medications
  • Cost, availability and access to medication
  • Patient preferences
  • Management needs
  • Drug regimen that optimizes medication adherence
• Selection of antidiabetic medications for cardiovascular and renal outcome improvement is the same with older people

• Lifestyle modification with Metformin is recommended for newly diagnosed individuals with diabetes mellitus or those with mild hyperglycemia
  • Metformin may be used as background therapy and may be combined with other medications in cases when therapeutic goal is not achieved with monotherapy alone
  • Other therapeutic agents (eg glucagon-like peptide-1 [GLP-1] receptor agonists, dipeptidyl peptidase-4 inhibitors [DPP-4], sodium-glucose linked transporter 2 [SGLT2] inhibitors, alpha-glucosidase inhibitors and sulfonylureas) may be used in patients with intolerance or contraindications to Metformin

• Combination therapy may be started in young adults (<40 years) with type 2 diabetes mellitus or in patients with HbA1c of  ≥1.5% above glycemic target at diagnosis according to the ADA and EASD 2022 consensus report and 2024 ADA guideline, or those not able to reach the therapeutic goal with monotherapy alone
  • Combination therapy is Metformin plus another antidiabetic (antihyperglycemic) agent
  • Fixed-dose formulations can improve medication compliance when combination therapy is used and can help achieve target glucose levels more rapidly

• Triple therapy is recommended for patients with suboptimal response to dual combination therapy
• Consider early combination therapy in individuals <40 years old with diabetes
• GLP-1 receptor agonists are preferred to insulin in most patients who need the greater glucose-lowering effect of an injectable medication
• Early introduction of insulin is considered if there is a presence of:
  • Ongoing catabolism (weight loss)
  • Symptoms of hyperglycemia
  • Very high HbA1c levels (>10%) or blood glucose levels (16.7 mmol/L or ≥300 mg/dL)

• Insulin is recommended in patients with extreme and symptomatic hyperglycemia
• Combination injectable therapy is initiated when basal insulin has been titrated to an acceptable fasting blood glucose level and HbA1c remains above normal or dose of basal insulin >0.5 U/kg/day
  
  • This approach involves using GLP-1 receptor agonist or dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist added to basal insulin or multiple doses of insulin
  • When  initiating combination injectable therapy, Metformin therapy should be continued while dosages of other medications are adjusted or discontinued
• A network meta-analysis showed that among the antidiabetic agents, GLP-1 receptor agonists and insulin regimens have the greatest reductions in HbA1c levels
  • GLP-1 receptor agonists including dual GIP and GLP-1 receptor agonist are preferred to insulin in most patients who need the a greater glucose-lowering effect of an injectable medication and should be considered in all individuals without contraindications prior to initiating insulin therapy

• GLP-1 receptor agonists or SGLT2 inhibitors with proven benefit should be considered in patients with multiple risk factors for or with established cardiovascular disease, heart failure or chronic kidney disease independent of background Metformin use and independent of baseline HbA1c
• Consider using a GLP-1 receptor agonist with proven benefit to reduce major adverse cardiovascular events, or an SGLT2 inhibitor with proven benefit to reduce major adverse cardiovascular events and heart failure and improve renal outcomes in the following individuals:
  • With established cardiovascular disease to reduce cardiovascular risk independent of baseline or glucose control
  • Without established cardiovascular disease but with multiple cardiovascular risk factors (eg ≥55 years old, smoking, hypertension, dyslipidemia, obesity, or albuminuria)
  • With coronary artery disease
  • An SGLT2 inhibitor with proven benefit to reduce major adverse cardiovascular events and heart failure and improve renal outcomes should be used in patients with heart failure to reduce heart failure hospitalization or cardiovascular death and those with chronic kidney disease (estimated glomerular filtration rate [eGFR] of ≥20 mL/min/1.73 m² and a UACR of ≥22.6 mg/mmol [≥200 mg/g]) to reduce cardiovascular and kidney failure risk
  • A GLP-1 receptor agonist with proven cardiovascular benefit to reduce major adverse cardiovascular events could be considered and should be continued until kidney transplantation is indicated in individuals with chronic kidney disease in whom an SGLT2 inhibitor is not tolerated or is contraindicated
    • GLP-1 receptor agonists are recommended in patients with chronic kidney disease with eGFR >15 mL/min/1.73 m² to achieve adequate glycemic control due to its low risk of hypoglycemia and beneficial effects on weight, cardiovascular risk and albuminuria 
• In individuals who are overweight and in obese patients, weight management of obesity through lifestyle modification, medications and/or surgery serves as a cornerstone for the treatment of diabetes mellitus
  • Reduction in body fat mass leads to better secretory function of Insulin
  • Effectively reduces morbidity and mortality in patients with type 2 diabetes mellitus
  • Clinical evidences show that GLP-1 receptor agonists, SGLT2 inhibitors and Tirzepatide are most effective for reducing body weight

Guidelines in Using Oral Antidiabetic (Antihyperglycemic) Agent in Diabetes Mellitus

• Therapeutic goals and drug choice should be individualized in patients with comorbidities
• Start oral antidiabetic agent at a low dose while stressing the need of diet and physical activity
• Daily dosing of oral antidiabetic agents may improve compliance
• In individuals with diabetes mellitus under stress (eg infection), short-term insulin therapy is recommended until recovery
• When treatment with single oral antidiabetic agent fails to achieve therapeutic goal, combination with another class of oral antidiabetic agents or basal insulin may be given

Intercurrent Illness (eg Any Illness, Trauma, and/or Surgery)

• Stress can aggravate glycemic control and may precipitate hyperglycemic crisis
• Frequent blood glucose monitoring is required; urine and blood ketone levels should also be checked in ketosis-prone patients
• Temporary adjustment of treatment is needed in patients with hyperglycemic crisis
  • Provide adequate fluid and caloric intake
  • Insulin may be temporarily needed by patients on non-insulin therapy or medical nutrition therapy alone

Hypoglycemia

• Primary limiting factor in glycemic management of type 1 and Insulin-treated type 2 diabetes mellitus
• Hypoglycemia can be classified as:
  • Level 1: Plasma glucose ≥54 mg/dL (3.0 mmol/L) to <70 mg/dL (3.9 mmol/L)
  • Level 2: Plasma glucose <54 mg/dL (3.0 mmol/L)
  • Level 3: Severe event characterized by altered mental and/or physical status requiring assistance for treatment of hypoglycemia, irrespective of glucose level
• Should be treated with glucose (15-20 g) or any form of carbohydrate as an alternative
  • IV glucose may be administered to treat severe hypoglycemia
  • Glucagon IM is recommended for patients at risk of level 2 or hypoglycemia
    • May be given to patients for the treatment of severe hypoglycemia (eg unable or unwilling to take carbohydrates by mouth) and can be given by family members or caregivers

Immunization

• Common preventable infectious diseases such as influenza and pneumonia are associated with high mortality and morbidity in older people and in patients with chronic diseases like diabetes mellitus
• Give influenza vaccine yearly to all patients with diabetes mellitus
• Give 23-valent pneumococcal polysaccharide vaccine (PPSV23) to all patients with diabetes mellitus aged 2-64 years old
  • In patients ≥65 years old, if pneumococcal conjugate vaccine (PCV13) is already given, this should be followed by a dose of PPSV23 vaccine at least a year after and at least 5 years after the last dose of PPSV23
• Administer two- or three-dose series of hepatitis B vaccine to unvaccinated individuals with diabetes mellitus aged 19-59 years old
  • Consider giving hepatitis B vaccine to unvaccinated individuals with diabetes mellitus ≥60 years old
• Single dose of respiratory syncytial virus (RSV) vaccine may be given in patients with diabetes mellitus ≥60 years old
• Booster dose of tetanus, diphtheria, and pertussis (Tdap) in all adults is recommended every 10 years
• Zoster vaccine is recommended in patients with diabetes mellitus ≥50 years old

Antidiabetic (Antihyperglycemic) Agents

Alpha-glucosidase Inhibitors (eg Acarbose, Miglitol, Voglibose)

• Indicated in treating patients with type 2 diabetes mellitus as monotherapy or as a combination therapy
  • May be used together with Insulin and have synergistic effect when given with other oral antidiabetic agents
  • Does not cause weight gain or hypoglycemia if used as monotherapy
• Most suitable in patients with moderately elevated glucose and HbA1c
• Reduce digestion rate of polysaccharides in the proximal small intestine by inhibiting α-glucosidase enzymes, which are essential for the release of glucose from more complex carbohydrates
  • Delay absorption of carbohydrate which lowers postprandial blood glucose and insulin levels
• One of the agents that primarily affects postprandial glucose
• Approximately lower HbA1c by 0.7-0.8% with monotherapy¹
• Less effective than Metformin or sulfonylureas
• Must be taken during meals; may cause bloating

Biguanides (eg Metformin)

• First-line treatment option for patients with type 2 diabetes mellitus due to its high efficacy, low cost, low side effects and hypoglycemia risk, and lack of associated weight gain
• Lower blood glucose through reduction in hepatic glucose production and does not stimulate insulin secretion thus usually not associated with hypoglycemia
• Affect both fasting plasma glucose and postprandial glucose
• May improve peripheral glucose disposal while it suppresses appetite and promotes weight reduction
• May be used as monotherapy which will approximately decrease HbA1c by 1%¹
• Have synergistic effect to further lower the blood glucose level when used in combination with other agents
• Able to increase insulin sensitivity and lower insulin requirements
• May cause modest weight loss or weight stability, as compared to other antidiabetic agents
• May be safely given to patients with eGFR of ≥30 mL/min/1.73 m²
  • Measure the patient’s eGFR prior to starting Metformin therapy
• To reduce cardiovascular risk, Metformin may be used: 
  • As an add-on therapy for patients with type 2 diabetes mellitus with atherosclerotic cardiovascular disease if additional glucose control is needed    
  • In patients with type 2 diabetes mellitus without atherosclerotic cardiovascular disease or severe target organ damage but with low or moderate risk
• Some studies have shown beneficial effect on cardiovascular disease outcomes (ie reduces LDL-C and TG levels)
• May also be given to prevent type 2 diabetes mellitus in patients with impaired glucose tolerance (IGT), IFG, or HbA1C of 5.7-6.4%, especially if BMI ≥35 kg/m², age <60 years, and women with GDM history 
• In the Asia-Pacific region, significant evidence supports the effectiveness of lifestyle intervention and pharmacologic therapy with Metformin in patients with impaired glucose tolerance
• Periodic vitamin B12 measurement should be considered in patients who are on long-term treatment with Metformin as it is associated with biochemical vitamin B12 deficiency, especially in those patients with anemia or peripheral neuropathy

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors (eg Alogliptin, Evogliptin, Gemigliptin, Linagliptin, Saxagliptin, Sitagliptin, Teneligliptin, Trelagliptin, Vildagliptin)

• Indicated as monotherapy or in combination with Metformin, sulfonylurea or thiazolidinedione for patients with type 2 diabetes mellitus as an adjunct to diet and exercise
  • When used in combination with Insulin, dose of Insulin or sulfonylurea should be decreased to lower the risk of hypoglycemia
• Decrease the rate of incretin inactivation which is usually released in the gut throughout the day and increased after meals
  • Incretins increase the release of insulin from pancreatic β-cells and decrease secretion of glucagon from pancreatic α-cells
• Affect both FPG and postprandial glucose
• Glucose-lowering efficacy is intermediate; reduce HbA1c approximately by 0.5-0.8% with monotherapy¹
• It was found in the VERIFY trial that initial combination of Metformin and Vildagliptin had a slower decline of glycemic control compared with Metformin alone or Vildagliptin added sequentially to Metformin
• Based on two large clinical trials involving patients with heart disease, it was found that Alogliptin and Saxagliptin may increase the risk of heart failure in patients with heart or kidney disease
• Based on the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study, Sitagliptin was not found to be associated with increased risk of heart failure
• Do not cause hypoglycemia or weight gain
  • May be given to patients if further gain in weight would exacerbate or cause significant problems
• May be taken without regard to food

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists (eg Albiglutide*, Dulaglutide, Exenatide, Liraglutide, Lixisenatide, Semaglutide)

• Possess endogenous GLP-1 activity but are resistant to DPP-4 enzyme breakdown, resulting in longer action
  • Increases insulin release when glucose concentration is elevated, alters gastric emptying, prevents postprandial rise in plasma glucagon and causes satiety leading to lower caloric intake and weight loss
• Have high to very high glycemic efficacy; approximately reduce HbA1c by 0.5-1.4% with monotherapy and lower predominantly fasting or postprandial glucose based on type (short or long acting) of GLP-1  receptor agonist¹
• Recommended in patients with established cardiovascular disease due to its cardiovascular benefit
  • GLP-1 receptor agonists with proven cardiovascular benefit include Dulaglutide, Liraglutide and Semaglutide
• Have intermediate to very high weight loss efficacy; may be used to treat obese patients with type 2 diabetes mellitus who are already on Metformin and/or sulfonylurea
  • Preferred antidiabetic agents in overweight and obese patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease 
  • Among GLP-1 receptor agonists, weight loss efficacy is as follows: Semaglutide >Liraglutide >Dulaglutide >Exenatide >Lixisenatide
• Used as an alternative to adding insulin therapy in patients who fail to reach target glucose level on dual therapy with Metformin and/or sulfonylurea
  • Dose of sulfonylurea should be reduced to lower the risk of hypoglycemia when combined with GLP-1 agonist
• Except for twice-daily Exenatide, all GLP-1 receptor agonists are contraindicated in patients with personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 
• Liraglutide may be used to further improve blood glucose level in obese patients with type 2 diabetes mellitus who fail to reach target glucose level even with Metformin and a thiazolidinedione
  • Liraglutide should also be considered in patients with long-standing suboptimally controlled type 2 diabetes mellitus and established atherosclerotic cardiovascular disease as it has been shown to reduce the risk of adverse cardiovascular events (eg heart attack, stroke and cardiovascular death) when added to standard care
  • Liraglutide is recommended in patients with type 2 diabetes mellitus and cardiovascular disease or with very high/high cardiovascular risk to reduce risk of death
• Exenatide immediate-release formulation must be given within 60 minutes before breakfast and dinner while Exenatide extended-release formulation can be given at any time of the day with or without meals
  • Not recommended for patients with ESRD or severe renal impairment
• Dulaglutide is a GLP-1 receptor agonist that is useful as an add-on therapy for patients within adequately controlled diabetes mellitus during oral monotherapy
• Semaglutide is an oral GLP-1 receptor agonist
  • Used as monotherapy when Metformin is intolerable or contraindicated
  • Used as add-on therapy for patients with diabetes mellitus treated with other antidiabetic agents

*Albiglutide is currently not available in the market

GLP-1 Receptor and Glucose-dependent Insulinotropic Polypeptide (GIP) Receptor Agonist (eg Tirzepatide)

• Tirzepatide is a once-weekly dual GLP-1 receptor and GIP receptor agonist subcutaneously given as an addition to diet and exercise for glycemic control improvement in adults with type 2 diabetes mellitus  
• Has a very high glucose- and weight-lowering efficacy
• In clinical trials comparing Tirzepatide with other antidiabetic agents, participants who were given the maximum recommended dose of 15 mg had lowering of their HbA1c by 0.5% more than Semaglutide, 0.9% more than Insulin degludec and 1% more than Insulin glargine 
• Results from a phase 3 trial (SURMOUNT-2) showed weight loss of 9.6% and 11.6% more than placebo and A1c lowering of 1.55% and 1.57% more than placebo after 72 weeks of therapy with 10 mg and 15 mg doses respectively 

Meglitinides/Non-Sulfonylurea Insulin Secretagogues (eg Mitiglinide, Nateglinide, Repaglinide)

• Useful in controlling postprandial glucose
• Short-acting insulin secretagogues that bind to a different site within the sulfonylurea receptor that stimulate secretion of insulin
• Approximately decrease HbA1c by 0.7-1.2% with monotherapy¹
• Must be administered more frequently because of short half-life as compared with sulfonylureas and fast absorption from the GI tract; peak level at 1 hour post-administration and eliminated within 4 to 6 hours
• May be used in combination with Metformin, thiazolidinediones, or alpha-glucosidase inhibitors
  • Concomitant use of Repaglinide and Gemfibrozil should be avoided due to higher risk of hypoglycemia
• Should be taken within 10 to 15 minutes before main meals
• May cause weight gain similar to sulfonylureas but has lower risk for hypoglycemia

Sodium-Glucose Linked Transporter/Co-transporter 2 (SGLT2) Inhibitors (eg Bexagliflozin, Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin, Luseogliflozin)

• SGLT2 inhibitors reduce reabsorption of glucose in the renal tubules leading to increased urinary excretion of glucose
• Indicated as monotherapy or in combination with Metformin, or as a second-line therapy, and in patients with atherosclerotic cardiovascular disease in whom heart failure is present or is of special concern
  • Preferred antidiabetic agents in overweight and obese patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease
• Have intermediate to high glucose-lowering efficacy; approximately decrease HbA1c by 0.4-0.8% with monotherapy¹
• SGLT2 inhibitors (eg Canagliflozin, Dapagliflozin, Empagliflozin and Sotagliflozin) have proven cardiovascular disease benefit and in cardiovascular outcome trials were shown to reduce heart failure and progression of chronic kidney disease
• In the Canagliflozin Cardiovascular Assessment Study (CANVAS) program, results showed that patients with established atherosclerotic cardiovascular disease treated with Canagliflozin had lower rates of major adverse cardiovascular events and lower risk of hospitalization for heart failure
• In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients - Remove Excess Glucose (EMPA-REG) clinical trial, individuals with type 2 diabetes mellitus with established cardiovascular disease who took Empagliflozin in addition to standard care have a lower rate of cardiovascular events, all-cause mortality and lower risk of hospitalization for heart failure (when compared to those who took placebo)
  • Recommended in patients with type 2 diabetes mellitus and cardiovascular disease to reduce the risk of death
• It has been found in the Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction (DECLARE-TIMI 58) trial that individuals with type 2 diabetes mellitus taking Dapagliflozin had a lower rate of cardiovascular death or hospitalization for heart failure
  • In this trial, individuals with type 2 diabetes mellitus who had multiple risk factors for or established atherosclerotic cardiovascular disease were randomly assigned to receive Dapagliflozin or placebo and results did not show any statistically significant difference in the overall rate of major adverse cardiovascular events between these two groups
  • The trial result also showed decrease in the risk of heart failure and adverse renal outcomes in a broad population of patients with type 2 diabetes
• SGLT2 inhibitors have proven cardiovascular disease benefit and in cardiovascular outcome trials were shown to reduce heart failure and progression of chronic kidney disease
• Other beneficial effects of SGLT2 inhibitors include reduction of fasting and 2-hour postprandial glucose levels,body weight, blood pressure and increases in HDL levels
• Found to be associated with increased risk of genitourinary infections and slightly increased LDL-C
• Canagliflozin was found in clinical trials to have increased incidence of bone fractures
• Patients taking Canagliflozin and Bexagliflozin have potential increased risk of amputation of the lower limb (mostly toes)
• Bexagliflozin was recently approved for the treatment for type 2 diabetes mellitus
  • Studies have shown Bexagliflozin significantly reduces HbA1c and was noninferior compared to Glimepiride and Sitagliptin; however, Bexagliflozin was not superior to placebo in terms of reducing major adverse cardiovascular events

Sulfonylureas/Insulin Secretagogues (eg second generation: Glibenclamide, Gliclazide, Glimepiride, Glipizide, Gliquidone; first generation: Chlorpropamide, Tolazamide, Tolbutamide)

• One of the 2nd-line options in patients intolerant of or with contraindication to Metformin
• One of the agents that primarily affects FPG
• Decrease plasma glucose up to 25% by increasing secretion of insulin from pancreatic beta cells
• Glucose-lowering efficacy is high; approximately reduce HbA1c by 0.4-1.3% with monotherapy¹
• Dose may be increased at intervals of 1 to 2 weeks until satisfactory glycemic control or maximum dose is reached
• Have similar effectiveness in controlling hyperglycemia
  • Should not combine two different sulfonylureas
• May be used in combination with other antidiabetic agents or insulin to improve glucose control
• Should not combine two different sulfonylureas
• May increase appetite and lead to weight gain
• May cause hypoglycemia due to their glucose-independent stimulation of insulin secretion and risk of hypoglycemia is higher in patients with renal impairment, liver cirrhosis and elderly
  • Glibenclamide causes the highest rate of hypoglycemia as compared to other sulfonylureas, and is not recommended in patients >60 years of age
  • Glipizide, Glimepiride and Gliclazide may have lower risk of hypoglycemia compared to other sulfonylureas
  Must be taken 30 minutes before meals
  • Glimepiride and Gliclazide may be taken just before meals

Thiazolidinediones (eg Pioglitazone, Rosiglitazone)

• A peroxisome proliferator-activated receptor-gamma agonist that increases insulin sensitivity of muscle, adipose tissue and liver to endogenous and exogenous insulin
• One of the agents that primarily affects FPG
• Have high glycemic efficacy; approximately reduce HbA1c by 0.5-0.9% when used as monotherapy¹
• Elevate HDL-C, lower BP, reduce inflammation markers, decrease hepatic steatosis, decrease carotid and coronary artery thickening and prevent restenosis after percutaneous transluminal coronary angioplasty
• Glycemic control may only be improved after 6 weeks and maximal effect may be seen up to 6 months after starting therapy
• May be an option in patients with type 2 diabetes mellitus with atherosclerotic cardiovascular disease   
  • Pioglitazone may be used as add-on therapy for patients with type 2 diabetes mellitus with atherosclerotic cardiovascular disease without heart failure if additional glucose control is required
• May be given in combination with sulfonylureas, Metformin, DPP-4 inhibitors, GLP-1 receptor agonists or SGLT2 inhibitors
• May cause fluid retention that is associated with risk of new or worsened heart failure
  • Thus contraindicated in patients with history of heart failure
  • Use with caution in combination with insulin due to an accentuated heart failure risk
• May cause weight gain or bone fracture especially in distal upper or lower limb but may not be a reason for discontinuation
  • Consider using lower doses and combination therapy with other antidiabetic agents that promote weight loss and sodium excretion to reduce weight gain and edema
• In 2015, US FDA concluded that Rosiglitazone monotherapy did not show additional CV risks in comparison to Metformin and a sulfonylurea combination based on an independent review of the RECORD trial
  • Hence, the restriction on prescribing and dispensing has been lifted
• The US FDA also removed the Risk Evaluation and Mitigation Strategy (REMS) as it is no longer needed to ensure that the benefits of Rosiglitazone therapy outweigh the risks

¹References: American Diabetes Association. Standards of care in diabetes - 2024. Diabetes Care. 2024; 2023 Task Force on Conceptual Model and Preventive Protocols, Working Group on Primary Care and Hong Kong Health Bureau. Hong Kong reference framework for diabetes care for adults in primary care settings; Diabetes Canada Clinical Practice Guideline Expert Committee. Pharmacologic glycemic management of type 2 diabetes in adults: 2020 update; 2020 Malaysian Endocrine and Metabolic Society clinical practice guidelines on management of type 2 diabetes mellitus.

Other Antidiabetic (Antihyperglycemic) Agents

Amylin Analog (eg Pramlintide)

• A synthetic analog of human amylin that slows gastric emptying without altering overall nutrient absorption, suppresses pancreatic secretion of glucagon, and enhances satiety that leads to decrease in caloric intake
  • Shown to induce weight loss and lower insulin dose requirements
• Used as an adjunct treatment in patients with type 1 and 2 diabetes mellitus who use mealtime insulin or have failed to reach target glucose control despite optimal insulin therapy
  • Indicated only in patients who are willing to add 2 to 4 injections and more frequent glucose monitoring in their regimen
• May be used in addition to prandial insulin therapy that may lower postprandial hyperglycemia, HbA1c and weight
  • Reduce HbA1c by 0.4% and weight by 1 kg after 6 months
• Approved for the treatment of type 1 diabetes mellitus
• May be used in combination with sulfonylurea and/or Metformin in type 2 diabetes mellitus
• Results in 50% reduction in preprandial, rapid-acting or short-acting insulin dosages
• Should be given immediately before each main meal
• Contraindicated in patients who are noncompliant with current insulin regimen, poorly adherent to the prescribed self-monitoring of blood glucose (SMBG), patients with HbA1c >9%, recurrent severe hypoglycemia requiring assistance during the past 6 months, with hypoglycemia unawareness, confirmed diagnosis of gastroparesis and in those that require use of drugs that stimulate GI motility or drugs that slow the intestinal absorption of nutrients

Bromocriptine

• A dopamine receptor agonist that modestly improves glycemic control in conjunction with diet and exercise
  • May be used in specific situations; does not lead to hypoglycemia and is associated with decreased rates of CV events
• Side effects may include orthostasis and nausea; not to be concomitantly used with antipsychotic agents

Colesevelam

• A bile acid sequestrant that modestly improves glucose levels as an adjunct to diet and exercise
  • May be used in specific situations; does not lead to hypoglycemia and reduces LDL-C level
• Side effects may include gastrointestinal intolerance and increase in triglyceride levels in patients with hypertriglyceridemia

Teplizumab

• A monoclonal antibody that binds to CD3 of T cells which increases the proportion of regulatory T cells and exhausted CD8+ T cells in the peripheral blood
• Recently approved agent to delay the onset of stage 3 type 1 diabetes mellitus in adults and pediatric patients ≥8 years old with stage 2 type 1 diabetes mellitus

Insulin

• Activates insulin receptors that can rapidly control hyperglycemia through increased glucose disposal, decreased hepatic glucose production and suppression of ketogenesis
• Has high to very high glycemic efficacy
• Required in all patients with type 1 diabetes mellitus and considered in patients with type 2 diabetes mellitus when noninsulin antidiabetic agents fail to reach target blood glucose level or when patient presents with severe hyperglycemia
• Considered as initial therapy in newly diagnosed type 2 diabetes mellitus with osmotic symptoms regardless of A1c or FPG, HbA1c >10% or FPG >13 mmol/L or as part of early insulinization regimen
• Insulin can be classified based on pharmacokinetic profiles in relation to meal times:
  • Prandial insulin has a rapid or short onset of action in controlling postprandial glucose excursion thus it is given pre-meal
  • Basal insulin has intermediate or long-acting pharmacokinetic profile that covers the basal insulin requirements in between meals and night time
  • Premixed insulin incorporates both the short- and intermediate-acting insulins in one preparation thus called biphasic insulin; covers both the postprandial glucose excursion and basal insulin needs
• May cause weight gain; risk of hypoglycemia is lower with analogs than with human insulin 
• Short-term use of insulin is considered in acute illness, surgery, stress, emergencies, severe metabolic decompensation (ie DKA, hyperosmolar hyperglycemic state) 
• Insulin regimen recommended for patients with type 1 diabetes mellitus consists of daily injections of long-acting basal insulin(or twice-daily injections of intermediate human insulin) and injections of rapid-acting insulin analog or short-acting human insulin before each meal
• May be administered through insulin pump or insulin pen device, pen needle or syringe
  • May be injected on the abdominal wall, thigh or the legs and upper arms 
• Use of continuous subcutaneous insulin infusion by infusion pump to deliver insulin in a more flexible and physiologic way can improve glucose control while decreasing hypoglycemia risk
• In type 2 diabetes mellitus, basal insulin may be initiated, followed by basal plus or basal bolus, then prandial or premixed insulin when FBG has reached targeted goal but HbA1c is still not achieved
• Insulin may be combined with oral agents (Metformin, sulfonylureas, glinides, DPP-4 inhibitors and thiazolidinediones)
  • Combination with sulfonylureas or glinides increases hypoglycemia risk
  • Combination with thiazolidinediones may cause weight gain, edema and possible congestive heart failure
  • If glycemic targets are not maintained on basal insulin combined with oral agents, treatment can be intensified with GLP-1 receptor agonists, SGLT2 inhibitors or prandial insulin

Long-acting/Basal Insulins (eg Insulin degludec, Insulin detemir, Insulin glargine, Insulin glargine U-100 and U-300)

• Treatment option of choice when starting insulin therapy
• Should be the first choice in managing patients with type 2 diabetes mellitus to target FPG
  • An effective option in controlling FPG in patients with type 2 diabetes mellitus and poor glycemic control
• Preferred over intermediate-acting neutral protamine Hagedorn (NPH) because they do not have a pronounced peak, have up to 24 hours of activity, associated with less weight gain, have lower day-to-day variability which results in fewer symptoms and lower nocturnal hypoglycemia
• Basal insulin restrains hepatic glucose production and limits hyperglycemia overnight and between meals
• Insulin degludec is associated with lower risk of severe hypoglycemia compared with Insulin glargine in patients with long-standing type 2 diabetes at high risk of cardiovascular disease

Intermediate-acting Insulin (eg NPH insulin)

• NPH insulin may be continued if patient reached target glucose level without having hypoglycemia and unacceptable glycemic excursions
• Preferred for gestational diabetes patients; though an RCT demonstrated that Insulin detemir was not inferior to NPH insulin in efficacy and safety

Rapid/Short-acting Insulins (eg Regular human insulin, Rapid-acting analogs [Insulin aspart, Insulin glulisine, Insulin lispro])

• Short- or rapid-acting insulin should be considered for postprandial hyperglycemia
  • Rapid-acting insulin usually requires addition of basal insulin
• Insulin analogs are favored if available because regular human insulin has inconsistent absorption which causes variable peak activity (2 to 4 hours), unpredictable postprandial glucose, 6 to 8 hours duration of action and possibility of delayed hypoglycemia
  • Regular human insulin has slow absorption and delayed onset of action that does not match normal insulin release in response to a meal, therefore must be given at least 30 minutes before a meal

Premixed Insulins (eg 70% NPH/30% regular, 70% Insulin aspart protamine/30% Insulin aspart, 50% Insulin aspart protamine/50% Insulin aspart, 75% Insulin lispro protamine/25% Insulin lispro, 50% Insulin lispro protamine/50% Insulin lispro, Insulin degludec 70%/Insulin aspart 30%)

• Offer components of both postprandial and intermediate-release glucose control
• Lacks dosage flexibility and limited to some extent in reaching blood glucose targets except if administered more frequently or in higher doses, which may increase hypoglycemia risk and weight gain
• Analog premixed insulins are preferred over human premixed insulins because of their faster onset of action, stable postprandial glucose control and lower variability in activity
• Insulin degludec 70%/Insulin aspart 30% is a novel soluble co-formulation that allows these molecules to coexist without affecting their individual pharmacodynamic profiles of rapid-acting Insulin aspart and long-acting Insulin degludec

Concentrated Insulin

• Insulin glargine U-300 and Insulin degludec U-100 and U-200 have more prolonged and stable pharmacokinetic and pharmacodynamic characteristics than Insulin glargine U-100 and Insulin detemir
  • U-300 and U-200 have higher doses of basal insulin administered per volume used
• U-500 regular insulin is 5 times more concentrated than U-100 regular insulin and has delayed onset and longer duration of action, possessing both prandial and basal properties
• U-200 rapid-acting Insulin lispro is also now available
• These formulations may improve compliance and comfort in patients with insulin resistance who require larger doses of insulin
  • To minimize risk of dosing errors, prefilled pens with or without vials are available

Inhaled Insulin

• Available for prandial use with a more limited dosing range
• Spirometry is required prior to and after starting inhaled Insulin therapy
  • Use of inhaled Insulin may result in reduced forced expiratory volume in 1 second (FEV₁)
• Not advisable to use in patients with chronic lung disease, those who smoke or who recently stopped smoking

Insulins and Analogs

• Studies have shown that a combination of basal insulin and GLP-1 receptor agonists is associated with less hypoglycemia and with weight loss but may be less tolerable and have a greater cost
  • Available once-daily fixed dual preparations of combination of basal insulin and GLP-1 receptor agonists are Insulin glargine plus Lixisenatide and Insulin degludec plus Liraglutide